The present invention relates to a method for enhancing cancer therapy by administering an effective amount of an antineoplastic modulator. Preferred antineoplastic modulators are propargylamines including aliphatic propargylamines and aromatic propargylamines. The invention also includes a pharmaceutical composition for enhancing the treatment of cancer comprising an effective amount of an antineoplastic modulator of the present invention in admixture with a suitable diluent or carrier.
Cancer is a collection of diseases involving inappropriate and unregulated growth of cells in the body. The aim of chemical therapy (chemotherapy) of cancer is to introduce a chemical (antineoplastic drug) which will kill the cancerous cells but will not damage normal cells. The early rationale for the development of conventional antineoplastic drugs was that such agents would act selectively on cells undergoing cell division; since cancerous cells were thought to be invariably dividing more rapidly than normal cells in the body, it was believed that this would offer some therapeutic selectivity. However, antineoplastic agents collectively have the lowest therapeutic indices of any class of drugs used in humans. This lack of selectivity leads to the severe side effects associated with cancer chemotherapy; the major dose-limiting consideration for use of these agents is toxicity to bone marrow. Furthermore, the poor selectivity of these agents means they must be used at sub-optimal doses. The latter, in turn, may cause the development of a variety of drug resistance traits by cancerous cells. Thus, many types of cancers are ultimately unresponsive to chemotherapy and are therefore incurable.
Notwithstanding such limitations, chemotherapy remains the only and thus the most important treatment option for disseminated cancers. Despite decades of effort to find more effective and less toxic agents, the poor response of patients to conventional anticancer drugs and the limitations arising from intrinsic or acquired drug-resistance continue to limit the chemotherapeutic approach. It is estimated that over 50% of patients with advanced cancer will fail to respond, or will relapse from their initial response to chemotherapy, and will thus ultimately succumb to their disease. Given the prevalence and severity of disseminated disease, improving the chemotherapeutic treatment modality nevertheless remains a crucial objective of cancer research (1).
One novel and potentially major means of improving the chemotherapeutic modality of cancer treatment would be to improve the selectivity of the currently-available agents. To the degree to which selectivity could be improved, such an approach would diminish the toxic side effects and allow treatment with more appropriate doses of antineoplastics which, in turn, would diminish the inadvertent selection of drug-resistance variants during treatment. If, in addition, such a strategy would circumvent drug-resistance traits of either the intrinsic or acquired types, it would diminish all of the major, known limitations to conventional cancer chemotherapy. Remarkably, such an approach has been developed and verified to have all of these advantages in experimental chemotherapeutic models (2-17). Termed the modulator approach for improving cancer chemotherapy, this novel strategy solves the major limitations otherwise associated with the use of conventional antineoplastics.
An antineoplastic modulator is a chemical which modifies the action of an antineoplastic drug, improving the selectivity, and therefore efficacy of the antineoplastic drug. An antineoplastic modulator acts, simultaneously, to advantage in three ways: i), it protects non-cancerous (normal) tissue from the toxic effects of the antineoplastic drug; ii), it increases the ability of the antineoplastic drug to kill cancerous cells, and iii), it suppresses the drug resistance traits exhibited by many cancerous cells.
The present inventors have prepared many novel propargylamines as described in U.S. Pat. Nos. 5,169,868 and 5,840,979. The inventors have shown that the novel propargylamines are useful as MAO-B inhibitors and are useful in treating various neuropsychiatric disorders including Parkinson""s disease, Alzheimer""s disease, depression, attention deficit disorder, hyperactive disorders as well as other aging-associated diseases.
Surprisingly, the present inventors have found that the propargylamines are also useful as antineoplastic modulators and can enhance the effect of antineoplastic drugs.
Broadly stated, the present invention relates to a method of enhancing cancer therapy by administering an effective amount of a propargylamine. The present inventors have shown that propargylamines enhance the killing of tumor cells by antineoplastic drugs and protect normal cells from the cytotoxic effects of antineoplastic drugs. Consequently, propargylamines are well-suited to enhance any chemotherapy regime and can increase the effectiveness while reducing the side-effects of cancer therapy.
In one aspect, the present invention relates to a method for enhancing the effect of an antineoplastic drug comprising administering an effective amount of a propargylamine to an animal in need thereof.
In another aspect, the present invention relates to a method of increasing the sensitivity of a tumor to an antineoplastic drug comprising administering an effective amount of propargylamine of the invention to an animal in need thereof.
In a further aspect, the present invention provides a method of protecting normal cells from the cytotoxic effects of an antineoplastic drug comprising administering an effective amount of a propargylamine of the invention to an animal in need thereof.
In a further aspect, the present invention relates to a method for treating cancer comprising administering an antineoplastic drug and an effective amount of a propargylamine of the invention to an animal in need thereof.
The present invention also includes a use of a propargylamine of the present invention for the preparation of a medicament to be used in the therapeutic methods described herein.
The present invention further includes a pharmaceutical composition useful for enhancing cancer therapy comprising an effective amount of a propargylamine of the invention in admixture with a suitable diluent or carrier.
The pharmaceutical compositions of the present invention may be useful in (i) enhancing the activity of an antineoplastic drug, (ii) increasing the sensitivity of a tumor to an antineoplastic drug and/or (iii) protecting normal cells from the cytotoxic effects of an antineoplastic drug.
The present invention also includes a pharmaceutical composition useful for treating cancer comprising an antineoplastic drug and an effective amount of a propargylamine of the present invention.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.